Post operative graft rejections are a major complication affecting the success of bone marrow and organ transplantations. However, through the use of immunosuppressive drug therapy, graft rejection in organ transplantation can be significantly reduced.
A wide variety of diseases can be characterized as "autoimmune diseases". Such diseases are similar to graft rejection, except that the rejection is of self tissue. Immunosuppressive therapy can also be of use in preventing this inappropriate self rejection.
One widely accepted immunosuppressant for the prevention of graft rejection is cyclosporin A (CsA). It is a natural product of fungal metabolism and has been demonstrated to have potent immunosuppressive activity in clinical organ transplantations. Calne, R. Y. et al., Br. Med. J. 282:934-936 (1981); White, D. J. C. Drugs 24:322-334 (1982). Although CsA is widely used in ummunosuppressant therapy, its usage (particularly in high dosage) is often accompanied by side effects which include nephrotoxicity, hepatotoxicity and other central nervous system disorders.
The following diseases have been treated with cyclosporin A with positive results, confirming the importance of the autoimmune component in these diseases and their effective treatment with compounds working by selective T-cell immune suppression similar to cyclosporin A.
1) Ophthalmology: Uveitis, Behcet's disease and Grave's ophthalmopathy. Weetman, A. P. et al., Lancet 486-489 (1982). Grave's opthalmopathy. Nussenblatt, R. B. et al., Lancet 235-238 (1983). Uveitis. French-Constant, C. et al., Lancet 454 (1983). Behcet's disease. Sanders, M. et al., Lancet 454-455 (1983). Behcet's disease. Note: Cyclosporin A is currently approved in Japan for the treatment of Behcet's disease, the first autoimmune disease indication for this compound.
2) Dermatology: Various autoimmune skin diseases including psoriasis. Zabel, P. et al., Lancet 343 (1984). Acute dermatomyositis. van Joost, T. et al., Arch. Dermatol 123:166-167 (1987). Atopic skin disease. (1987). Atopic skin disease. Appleboom, T. et al., Amer. J. Med. 82:866-867 (1987). Scleroderma. Logan, R. A. and R. D. R. Camo, J. Roy. Soc. Med 81:417-418 (1988). Eczema. Griffiths, C. E. M. et al., Brit. Med. J. 293:731-732 (1986). Psoriasis. Ellis, C. N. et al., J. Amer. Med. Assoc. 256:3110-3116 (1986). Psoriasis.
3) Hematology: Various diseases including anemia. Toetterman, T. H. et al., Lancet, 693 (1984). Pure red cell aplasia (PRCA). Stryckmans, P. A. et al., New Engl. J. Med. 310:655-656 (1984). Aplastic anemia. Gluckman, E. et al., Bone Marrow Transplant 3 Suppl. 1, 241 (1988). Aplastic anemia.
4) Gastroenterology/Heptatology: Primary cirrhosis, autoimmune hepatitis, ulcerative colitis, Crohn's disease and other gastrointestinal autoimmune diseases. Wiesner, R. H. et al., Heptalogy 7:1025, Abst. #9, (1987). Primary biliary cirrhosis. Hyams, J. S. et al., Gastroenterology 93:890-893 (1987). Autoimmune hepatitis. Allison, M. C. et al., Lancet, 902-903 (1984). Crohn's disease. Brynskov, J. et al., Gastroenterology 92:1330 (1987). Crohn's disease. Porro, G. B. et al., Ital. J. Gastroenterol. 19:40-41 (1987). Ulcerative colitis.
5) Neurology: Amyotrophic lateral sclerosis (ALS, "Lou Gehrig's disease"), myasthenia gravis and multiple sclerosis. Appel, S. H. et al., Arch. Neurol. 45:381-386 (1988). ALS. Tindall, R. S. A. et al., New Engl. J. Med. 316:719-724 (1987). Myasthenia gravis. Ann. Neurol. 24, No. 1, p. 169,m Abstract P174 (1988). Multiple sclerosis. Dommasch, D. et al., Neurology 38 Suppl. 2, 28-29 (1988). Multiple sclerosis.
6) Nephrotic Syndrome: Nephrotic syndrome, membranoproliferative glomerulonephritis (MPGN) and related diseases. Watzon, Ar. R. et al., Clin. Nephrol. 25:273-274 (1986). Nephrotic syndrome. Tejani, A. et al., Kidney Int. 33:729-734 (1988). Nephrotic syndrome. Meyrier, A. et al., Transplat Proc. 20, Suppl. 4 (Book III), 259-261 (1988). Nephrotic syndrome. LaGrue, G. et al., Nephron. 44:382--382 (1986). MPGN.
7) Rheumatoid Arthritis (RA) Harper, J. I. et al., Lancet 981-982 (1984). RA Van Rijthoven, A. W. et al., Ann. Rheum. Dis. 45:726-731 (1986). RA. Dougados, M. et al., Ann. Rheum. Dis. 47:127-133 (1988). RA.
8) Insulin-Dependent Diabetes Mellitus (IDDM) Stiller, C. R. et al., Science 223:1362-1367 (1984). IDDM. Assan, R. et al., Lancet, 67-71 (1985). IDDM. Bougneres, P. F. et al., New Engl. J. Med. 318:663-670 (1988). IDDM. Diabetes 37:1574-1582 (1988). IDDM.
Many veterinary diseases are also characterized as autoimmune diseases. Autoimmune diseases such as those listed above have been observed in mammals. Papa, F. O. et al., Equine Vet. J. 22:145-146 (1990) infertility of autoimmune origin in the stallion; Gorman, N. T. and L. L. Werner, Brit. Vet. J. 142:403-410, 491-497 and 498-505 (1986) immune mediated diseases of cats and dogs; Georg, L. W. and S. L. White, Vet. Clin. North Amer. 6:203-213 (1984) autoimmune skin diseases in large mammals; Bennett, D., In. Pract. 6:74-86 (1984) autoimmune diseases in dogs; Halliwell, R. E., J. Amer. Vet. Assoc. 181:1088-1096 (1982) autoimmune diseases in domesticated animals.
The mechanism by which CsA causes immunosuppression has been established. In vitro, CsA inhibits the release of lymphokines, such as interleukin 2 (IL-2) [Bunjes, D. et al., Eur. J. Immunol. 11:657-661 (1981)]and prevents clonal expansion of helper and cytotoxid T cells [Larsson, E. J. Immunol. 124:2828-2833 (1980)]. CsA has been shown to bind the cytosolic protein, cyclophilin, and inhibit the prolyl-peptidyl cis-trans isomerase (PPIase) activity of that protein. Fischer, G. et al., Nature 337:476-578 (1989); Takahashi, N. et al., Nature 337:473-475 (1989). The PPIases may mediate T cell activation by catalyzing the rotomerization of peptide bonds of prolyl residues.
Recently, a second natural product isolated from Streptomyces, referred to as FK-506, has been demonstrated to be a potent immunosuppressive agent. Tanaka, H. et al., J. Am. Chem. Soc. 109:5031-5033 (1987). FK-506 inhibits IL-2 production, inhibits mixed lymphocyte culture response and inhibits cytotoxic T-cell generation in vitro at 100 times lower concentration than cyclosporin A. Kino, T. et al., J. Antibiot. 15:1256-1265 (1987). FK-506 also inhibits PPIase activity, but is structurally different from CsA and binds to a binding protein (FKBP) distinct from cyclophilin. Harding, M. W. et al., Nature 341:758-760 (1989); Siekierka, J. J., Nature 341:755-757 (1989).